Chlorambucil

Identification

Summary

Chlorambucil is a chemotherapy agent used in the management of chronic lymphocytic leukemia and malignant lymphomas.

Brand Names
Leukeran
Generic Name
Chlorambucil
DrugBank Accession Number
DB00291
Background

A nitrogen mustard alkylating agent used as antineoplastic agent for the treatment of various malignant and nonmalignant diseases. Although it is less toxic than most other nitrogen mustards, it has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (Merck Index, 11th ed)

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 304.212
Monoisotopic: 303.079284271
Chemical Formula
C14H19Cl2NO2
Synonyms
  • 4-(p-bis(beta-chloroethyl)aminophenyl)butyric acid
  • 4-(p-bis(β-chloroethyl)aminophenyl)butyric acid
  • 4-[p-[bis(2-chloroethyl)amino]phenyl]butyric acid
  • Ambochlorin
  • Chlorambucil
  • Chloraminophen
  • Clorambucilo
  • gamma-[p-di(2-chloroethyl)aminophenyl]butyric acid
  • N,N-di-2-chloroethyl-gamma-p-aminophenylbutyric acid
  • N,N-di-2-chloroethyl-γ-p-aminophenylbutyric acid
  • Phenylbutyric acid nitrogen mustard
  • γ-[p-di(2-chloroethyl)aminophenyl]butyric acid
External IDs
  • CB-1348
  • NCI-3088
  • NSC-3088

Pharmacology

Indication

For treatment of chronic lymphatic (lymphocytic) leukemia, childhood minimal-change nephrotic syndrome, and malignant lymphomas including lymphosarcoma, giant follicular lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas, and Waldenström’s Macroglobulinemia.

Pharmacology
Accelerate your drug discovery research with the industry’s only fully connected ADMET dataset, ideal for:
Machine Learning
Data Science
Drug Discovery
Accelerate your drug discovery research with our fully connected ADMET dataset
Learn more
Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
Contraindications & Blackbox Warnings
With our commercial data, access important information on dangerous risks, contraindications, and adverse effects.
Learn more
Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects
Learn more
Pharmacodynamics

Chlorambucil is an antineoplastic in the class of alkylating agents that is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Mechanism of action

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.

TargetActionsOrganism
UDNA
cross-linking/alkylation
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

99%

Metabolism
Not Available
Route of elimination

Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard. The pharmacokinetic data suggests that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.

Half-life

1.5 hours

Clearance

Not Available

Adverse Effects
Medicalerrors
Reduce medical errors
and improve treatment outcomes with our comprehensive & structured data on drug adverse effects.
Learn more
Reduce medical errors & improve treatment outcomes with our adverse effects data
Learn more
Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Chlorambucil is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Chlorambucil.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Chlorambucil.
AcetazolamideThe therapeutic efficacy of Acetazolamide can be decreased when used in combination with Chlorambucil.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Chlorambucil.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Chlorambucil.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Chlorambucil.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Chlorambucil.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Chlorambucil.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Chlorambucil.
Interactions
Improve patient outcomes
Build effective decision support tools with the industry’s most comprehensive drug-drug interaction checker.
Learn more
Food Interactions
  • Avoid echinacea. Echinacea should be used with caution, if at all, in patients receiving therapeutic immunosuppressants. Monitor for reduced efficacy of the immunosuppressant during concomitant use.
  • Drink plenty of fluids.
  • Take on an empty stomach. Co-administration with food decreases bioavailability.

Products

Products
Comprehensive & structured drug product info
From application numbers to product codes, connect different identifiers through our commercial datasets.
Learn more
Easily connect various identifiers back to our datasets
Learn more
Product Images
International/Other Brands
Celkeran (Celon) / Chloraminophène (Techni-Pharma)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LeukeranTablet, film coated2 mg/1OralPhysicians Total Care, Inc.1985-02-132012-06-30US flag
LeukeranTablet2 mgOralAspen Pharmacare Canada Inc.1957-12-31Not applicableCanada flag
LeukeranTablet, film coated2 mg/1OralGlaxosmithkline Inc1985-02-132014-06-30US flag0173 063520180907 15195 s662c
LeukeranTablet, film coated2 mg/1OralAspen Global Inc.1985-02-13Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
LEUKERAN 2 MG TABLET, 25 ADETChlorambucil (2 mg)TabletOralVLD DANIŞMANLIK TIBBİ ÜRÜNLER VE TANITIM HİZMETLERİ LTD. ŞTİ.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
L01AA02 — Chlorambucil
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as nitrogen mustard compounds. These are compounds having two beta-haloalkyl groups bound to a nitrogen atom.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Nitrogen mustard compounds
Direct Parent
Nitrogen mustard compounds
Alternative Parents
Dialkylarylamines / Aniline and substituted anilines / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organochlorides / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
show 1 more
Substituents
Alkyl chloride / Alkyl halide / Amine / Amino acid / Amino acid or derivatives / Aniline or substituted anilines / Aromatic homomonocyclic compound / Benzenoid / Carbonyl group / Carboxylic acid
show 14 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
tertiary amino compound, monocarboxylic acid, organochlorine compound, aromatic amine, nitrogen mustard (CHEBI:28830)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
18D0SL7309
CAS number
305-03-3
InChI Key
JCKYGMPEJWAADB-UHFFFAOYSA-N
InChI
InChI=1S/C14H19Cl2NO2/c15-8-10-17(11-9-16)13-6-4-12(5-7-13)2-1-3-14(18)19/h4-7H,1-3,8-11H2,(H,18,19)
IUPAC Name
4-{4-[bis(2-chloroethyl)amino]phenyl}butanoic acid
SMILES
OC(=O)CCCC1=CC=C(C=C1)N(CCCl)CCCl

References

Synthesis Reference

Phillips, A. P. and Mentha, J.W.; U.S.Patent 3,046,301; July 24, 1962; assigned to Burroughs Wellcome & Co. (U.S.A.) Inc.

US2944079
General References
  1. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. [PubMed:11114313]
  2. Yang K, Tan J, Wu T: Alkylating agents for Waldenstrom's macroglobulinaemia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD006719. doi: 10.1002/14651858.CD006719.pub3. [PubMed:19160296]
  3. Foon KA, Hallek MJ: Changing paradigms in the treatment of chronic lymphocytic leukemia. Leukemia. 2010 Mar;24(3):500-11. doi: 10.1038/leu.2009.266. Epub 2009 Dec 24. [PubMed:20033051]
Human Metabolome Database
HMDB0014436
KEGG Drug
D00266
KEGG Compound
C06900
PubChem Compound
2708
PubChem Substance
46506842
ChemSpider
2607
BindingDB
50003677
RxNav
2346
ChEBI
28830
ChEMBL
CHEMBL515
ZINC
ZINC000000001115
Therapeutic Targets Database
DNC001110
PharmGKB
PA448926
PDBe Ligand
CBL
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Chlorambucil
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
3csj
MSDS
Download (74.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)1
4CompletedTreatmentUveitis1
4TerminatedTreatmentChronic Lymphocytic Leukaemia (CLL)1
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)3
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma1
3Active Not RecruitingTreatmentLeukemia, Lymphocytic, Chronic, B-Cell1
3CompletedTreatmentB-Cell Chronic Lymphocytic Leukemia1
3CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)5
3CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Lymphoma, Small-Cell1
3CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma1

Pharmacoeconomics

Manufacturers
  • Smithkline beecham corp dba glaxosmithkline
Packagers
  • Excella GmbH
  • GlaxoSmithKline Inc.
  • Physicians Total Care Inc.
Dosage Forms
FormRouteStrength
TabletOral
TabletOral2 mg
Tablet, film coatedOral2 mg/1
Tablet, film coatedOral
Pill
Tablet, coatedOral
Prices
Unit descriptionCostUnit
Leukeran 2 mg tablet3.92USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)65 °CPhysProp
water solubility1.24E+004 mg/LNot Available
logP1.70HANSCH,C ET AL. (1995), pH 7.4
pKa5.75HANSCH,C & LEO,AJ (1987)
Predicted Properties
PropertyValueSource
Water Solubility0.0773 mg/mLALOGPS
logP3.81ALOGPS
logP3.94ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)4.46ChemAxon
pKa (Strongest Basic)1.72ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area40.54 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity79.68 m3·mol-1ChemAxon
Polarizability31.98 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9739
Blood Brain Barrier+0.7889
Caco-2 permeable+0.5734
P-glycoprotein substrateNon-substrate0.6721
P-glycoprotein inhibitor INon-inhibitor0.9394
P-glycoprotein inhibitor IINon-inhibitor0.9222
Renal organic cation transporterNon-inhibitor0.6185
CYP450 2C9 substrateNon-substrate0.7651
CYP450 2D6 substrateNon-substrate0.744
CYP450 3A4 substrateNon-substrate0.6044
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.909
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9576
Ames testAMES toxic0.9107
CarcinogenicityNon-carcinogens0.7851
BiodegradationNot ready biodegradable0.9378
Rat acute toxicity3.5709 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6531
hERG inhibition (predictor II)Non-inhibitor0.8609
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.25 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-0udi-2491000000-ddb7d5da8316562dba36
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0zfr-0519000000-1bca00472dfc8c30a465

Targets

Drugtargets
Accelerate your drug discovery research
with our fully connected ADMET & drug target dataset.
Learn more
Accelerate your drug discovery research with our ADMET & drug target dataset
Learn more
Kind
Nucleotide
Organism
Humans
Pharmacological action
Unknown
Actions
Cross-linking/alkylation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Begleiter A, Mowat M, Israels LG, Johnston JB: Chlorambucil in chronic lymphocytic leukemia: mechanism of action. Leuk Lymphoma. 1996 Oct;23(3-4):187-201. [PubMed:9031099]
  4. Kashiwazaki G, Bando T, Shinohara K, Minoshima M, Kumamoto H, Nishijima S, Sugiyama H: Alkylation of a human telomere sequence by heterotrimeric chlorambucil PI polyamide conjugates. Bioorg Med Chem. 2010 Apr 15;18(8):2887-93. doi: 10.1016/j.bmc.2010.03.011. Epub 2010 Mar 10. [PubMed:20350810]
  5. Bielawska A, Bielawski K, Muszynska A: Synthesis and biological evaluation of new cyclic amidine analogs of chlorambucil. Farmaco. 2004 Feb;59(2):111-7. [PubMed:14871502]
  6. Minoshima M, Bando T, Shinohara K, Sugiyama H: Molecular design of sequence specific DNA alkylating agents. Nucleic Acids Symp Ser (Oxf). 2009;(53):69-70. doi: 10.1093/nass/nrp035. [PubMed:19749264]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
S-nitrosoglutathione binding
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name
GSTP1
Uniprot ID
P09211
Uniprot Name
Glutathione S-transferase P
Molecular Weight
23355.625 Da
References
  1. Parker LJ, Ciccone S, Italiano LC, Primavera A, Oakley AJ, Morton CJ, Hancock NC, Bello ML, Parker MW: The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants. J Mol Biol. 2008 Jun 27;380(1):131-44. doi: 10.1016/j.jmb.2008.04.066. Epub 2008 May 4. [PubMed:18511072]
  2. Zhang J, Lou YJ: Relationship between activation of microsomal glutathione S-transferase and metabolism behavior of chlorambucil. Pharmacol Res. 2003 Dec;48(6):623-30. [PubMed:14527828]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibit...
Gene Name
SLCO1A2
Uniprot ID
P46721
Uniprot Name
Solute carrier organic anion transporter family member 1A2
Molecular Weight
74144.105 Da
References
  1. Kullak-Ublick GA, Glasa J, Boker C, Oswald M, Grutzner U, Hagenbuch B, Stieger B, Meier PJ, Beuers U, Kramer W, Wess G, Paumgartner G: Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas. Gastroenterology. 1997 Oct;113(4):1295-305. [PubMed:9322525]

Drug created on June 13, 2005 13:24 / Updated on May 06, 2021 06:19